Mastocytosis is a disease of disordered mast cell proliferation which affects all ages. Clinical presentation and prognosis depends on the category of disease, which ranges between a benign and self-limited skin disease to more aggressive forms associated with hematologic disorders. The most common sites of mast cell accumulation observed in patients with mastocytosis are skin and bone marrow. The extent of skin involvement correlates with tryptase levels and pathology. Although overproduction of mast cell growth factors does not appear to be responsible for development of skin lesions, immunohistochemical characterization of mast cell aggregates in bone marrow reveal that they contain stem cell factor, which may act as an autocrine growth and differentiation factor. Mast cell lesions in the bone marrow may be associated with benign lymphoid aggregates. Single cell studies of hematopoietic lineages for activating codon 816 c-kit mutations, which we first identified in patients with mastocytosis, revealed the presence of c-kit mutations in B-cells and monocytes in addition to mast cells. These observations provided evidence that systemic mastocytosis is a disorder of the hematopoietic stem cell and bears striking similarities to myeloproliferative disorders in its pathogenesis. Gene microarray studies are in progress to elucidate the patterns of altered gene expression in bone marrow cells carrying c-kit mutations. In some cases, mastocytosis has an aggressive and ultimately fatal course; a successful approach to treatment for aggressive disease remains elusive. We have thus developed a short term in vitro cytotoxicity assay to screen the effects of novel chemotherapeutics and signal transduction inhibitors on bone marrow mast cells. Using this assay, we have found that STI571, a tyrosine kinase and Kit inhibitor recently approved by FDA for the treatment of chronic myeloid leukemia, does not show preferential cytotoxicity on mast cells bearing codon 816 c-kit mutation. These results complement those obtained from in vitro phosphorylation studies, where the drug preferentially inhibits the wild type Kit but not Kit with codon 816 mutations. The efficacy of bone marrow transplantation in patients with severe bone marrow disease is currently being investigated. Under a joint clinical protocol with NHLBI, three patients with advanced mastocytosis received a low-intensity conditioning peripheral blood stem cell transplantation. Complete donor myeloid and lymphoid engraftment was achieved in two patients who responded favorably to the treatment. These patients also showed evidence of graft-vs-mast cell effect. Studies to understand and counteract the mechanisms involved in mast cell degranulation are hampered by the lack of human mast cell lines bearing functional receptors for IgE. We have established the only human mast cell lines, named LAD1-5, bearing functional IgE and IgG receptors by culturing bone marrow aspirate mast cells from a patient with mast cell leukemia. It is expected that LAD mast cell lines will facilitate new discoveries to diagnose and treat allergic and mast cell disorders.